Crystalline sulfonamide-containing indole compound and process for preparing the same

ABSTRACT

A crystalline form of N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having a diffraction peak at a diffraction angle (2θ±0.2°) of 19.1° in a powder X-ray diffraction.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a 37 CFR § 1.53(b) divisional of U.S.application Ser. No. 10/571,279 filed Dec. 26, 2006, which claimspriority on PCT International Application No. PCT/JP2004/012649 filedSep. 1, 2004, which in turn claims priority on Japanese PatentApplication No. P2003-318953 filed Sep. 10, 2003. The entire contents ofeach of these application is here by incorporated by reference.

TECHNICAL FIELD

The present invention relates to crystalline sulfonamide-containingindole compound which are useful as antitumor agents with angiogenesisinhibitory action, and to a process for preparing the same.

BACKGROUND ART

Sulfonamide-containing indole compounds are useful as antitumor agentswith angiogenesis inhibitory action, and among them, an especiallynotable antitumor effect is exhibited byN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide(hereinafter referred to as “compound (5b)”) (see Patent document 1). Aprocess for preparing the compound (5b) is disclosed in Example 1 ofPatent document 1.

[Patent document 1] WO00/50395

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention

Upon several test runs of Example 1 of Patent document 1, the presentinventors have found that it is not always possible to obtain consistentcrystals. The active ingredient of a drug must be stably supplied as aproduct of consistent quality. Therefore, when the active ingredient ofa drug is obtained as a crystalline substance, it preferably consists ofa single crystal form and has satisfactory physical properties such asstability against light and other influences. It is also desirable todevelop a process for stable production of such crystals on anindustrial scale. It is therefore an object of the present invention toprovide crystals of the compound (5b) which consist of a single crystalform, and a process for preparing the same.

Means for Solving the Problems

As a result of much avid research, the present inventors have discoveredthat a single crystal form of the compound (5b) can be obtained by usinga specific solvent during crystallization of the compound (5b), and havesucceeded in completing this invention.

Specifically, the present invention provides the following [1] to [30].

[1] A crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having adiffraction peak at a diffraction angle (2θ±0.2°) of 11.4° in a powderX-ray diffraction.

[2] A crystalline form (Form C) according to [1] further having adiffraction peak at a diffraction angle (2θ±0.20) of 19.1° in a powderX-ray diffraction.

[3] A crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having anabsorption peak at a wavenumber of 1410±1 cm⁻¹ in an infrared absorptionspectrum (KBr).

[4] A crystalline form (Form C) according to [3] further having anabsorption peak at a wavenumber of 1443±1 cm⁻¹ in an infrared absorptionspectrum (KBr).

[4-2] A crystalline form (Form C) according to [1] or [2] having anabsorption peak at a wavenumber of 1410±1 cm⁻¹ in an infrared absorptionspectrum (KBr).

[4-3] A crystalline form (Form C) according to [4-2] further having anabsorption peak at a wavenumber of 1443±1 cm⁻¹ in an infrared absorptionspectrum (KBr).

[5] A crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having apeak at a chemical shift of approximately 143.4 ppm in a ¹³C solid stateNMR spectrum.

[6] A crystalline form (Form C) according to [5] further having a peakat a chemical shift of approximately 131.1 ppm in a ¹³C solid state NMRspectrum.

[6-2] A crystalline form (Form C) according to any one of [1] to [4-3]having a peak at a chemical shift of approximately 143.4 ppm in a ¹³Csolid state NMR spectrum.

[6-3] A crystalline form (Form C) according to [6-2] further having apeak at a chemical shift of approximately 131.1 ppm in a ¹³C solid stateNMR spectrum.

[7] A process for preparing a crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto any one of [1] to [6-3], characterized in thatN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide iscrystallized using a simple solvent selected from the group consistingof n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, s-butylalcohol, t-butyl alcohol and water, or a mixed solvent thereof as acrystallization solvent.

[8] A process according to [7], wherein the crystallization solvent is asimple solvent of isopropyl alcohol or s-butyl alcohol, or a mixedsolvent of s-butyl alcohol and water or a mixed solvent of isopropylalcohol and water.

[9] A process according to [7], wherein the crystallization solvent is amixed solvent of s-butyl alcohol and water (volume ratio=3:1-5:1) or amixed solvent of isopropyl alcohol and water (volume ratio=9:1-10:1).

[10] A process according to [7], wherein the crystallization solvent isa mixed solvent of s-butyl alcohol and water (volume ratio=3.9:1-4.1:1).

[11] A process according to [7], whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedand dissolved in a solvent and then crystallized.

[12] A process according to [7], whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedand dissolved in a solvent and then crystallized by gradual cooling.

[13] A process for preparing a crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto any one of [1] to [6-3], characterized in thatN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedat 80-130° C.

[14] A process for preparing a crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto any one of [1] to [6-3], characterized in thatN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedand stirred in water at 60-90° C.

[15] A process for preparing a crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto any one of [1] to [6-3], characterized in that a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate areheated at 80-130° C.

[16] A process for preparing a crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto any one of [1] to [6-3], characterized in that a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate areheated and stirred in water at 60-90° C.

[17] A process for preparing a crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto any one of [1] to [6-3], characterized in that a mixture comprising acrystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide anhydrateand a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate areheated at 80-130° C.

[18] A process for preparing a crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto any one of [1] to [6-3], characterized in that a mixture comprising acrystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide anhydrateand a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate areheated and stirred in water at 60-90° C.

[19] A crystalline form (Form A) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydratehaving a diffraction peak at a diffraction angle (2θ±10.2°) of 8.5° in apowder X-ray diffraction.

[20] A crystalline form (Form A) according to [1,9] further having adiffraction peak at a diffraction angle (2θ±0.2°) of 25.80 in a powderX-ray diffraction.

[21] A crystalline form (Form A) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydratehaving an absorption peak at a wavenumber of 616±1 cm⁻¹ in an infraredabsorption spectrum (KBr).

[22] A crystalline form (Form A) according to [21] further having anabsorption peak at a wavenumber of 802±1 cm⁻¹ in an infrared absorptionspectrum (KBr).

[22-2] A crystalline form (Form A) according to [1,9] or [20] having anabsorption peak at a wavenumber of 616±1 cm⁻¹ in an infrared absorptionspectrum (KBr).

[22-3] A crystalline form (Form A) according to [22-2] further having anabsorption peak at a wavenumber of 802±1 cm⁻¹ in an infrared absorptionspectrum (KBr).

[23] A crystalline form (Form A) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydratehaving a peak at a chemical shift of approximately 134.7 ppm in a ¹³Csolid state NMR spectrum.

[24] A crystalline form (Form A) according to claim 23 further having apeak at a chemical shift of approximately 126.3 ppm in a ¹³C solid stateNMR spectrum.

[24-2] A crystalline form (Form A) according to [1,9] to [22-3] having apeak at a chemical shift of approximately 134.7 ppm in a ¹³C solid stateNMR spectrum.

[24-3] A crystalline form (Form A) according to [24-2] further having apeak at a chemical shift of approximately 126.3 ppm in a ¹³C solid stateNMR spectrum.

[25] A pharmaceutical composition comprising a crystalline formaccording to any one of [1] to [6-3].

[26] An angiogenesis inhibitor comprising a crystalline form accordingto any one of [1] to [6-3].

[27] An antitumor agent, pancreatic cancer therapeutic agent, colorectalcancer therapeutic agent, gastric cancer therapeutic agent, breastcancer therapeutic agent, prostate cancer therapeutic agent, lung cancertherapeutic agent, ovarian cancer therapeutic agent, cancer metastasisinhibitor, diabetic retinopathy therapeutic agent, rheumatoid arthritistherapeutic agent or angioma therapeutic agent, comprising a crystallineform according to any one of [1] to [6-3].

[28] A method of preventing or treating a disease for which angiogenesisinhibition is effective, comprising administering to a patient, apharmacologically effective amount of a crystalline form according toany one of [1] to [6-3].

[29] A method of preventing or treating antitumor, pancreatic cancer,colorectal cancer, gastric cancer, breast cancer, prostate cancer, lungcancer, ovarian cancer, cancer metastasis, diabetic retinopathy,rheumatoid arthritis or angioma, comprising administering to a patient,a pharmacologically effective amount of a crystalline form according toany one of [1] to [6-3].

[30] Use of a crystalline form according to any one of [1] to [6-3] forthe manufacture of an antitumor agent, pancreatic cancer therapeuticagent, colorectal cancer therapeutic agent, gastric cancer therapeuticagent, breast cancer therapeutic agent, prostate cancer therapeuticagent, lung cancer therapeutic agent, ovarian cancer therapeutic agent,cancer metastasis inhibitor, diabetic retinopathy therapeutic agent,rheumatoid arthritis therapeutic agent or angioma therapeutic agent.

Effect of the Invention

According to the preparing process of the invention, it is possible toeasily prepare crystals (Form C) consisting of a single crystal form ofthe compound (5b) on an industrial scale. The respective crystals (FormA and Form C) of the invention can be prepared as a single crystal formby crystallization or the like and have satisfactory propertiesincluding stability to light, rendering them suitable for use as theactive ingredient of an antitumor agent. The crystals, Form A are alsouseful as an intermediate for preparing the crystals, Form C by athermal transition method.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a drawing representing a powder X-ray diffraction pattern ofthe crystals obtained in Example 3A.

FIG. 2 is a drawing representing a powder X-ray diffraction pattern ofthe crystals obtained in Example 1B.

FIG. 3 is a drawing representing a powder X-ray diffraction pattern ofthe crystals obtained in Example 1C.

FIG. 4 is a drawing representing a powder X-ray diffraction pattern ofthe crystals obtained in Example 1F.

FIG. 5 is a drawing representing a ¹³C solid state NMR spectrum of thecrystals obtained in Example 1C.

FIG. 6 is a drawing representing a ¹³C solid state NMR spectrum of thecrystals obtained in Example 1F.

FIG. 7 is a drawing representing an infrared absorption spectrum (KBr)of the crystals obtained in Example 1C.

FIG. 8 is a drawing representing an infrared absorption spectrum (KBr)of the crystals obtained in Example 1F.

FIG. 9 is a drawing representing a powder X-ray diffraction pattern ofthe crystals obtained in Example 1E.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be explained in greater detail. Thecrystals of the invention are crystals (Form A and Form C) of thecompound (5b) having the features described below. The measurementconditions for powder X-ray diffraction, infrared absorption spectrum(KBr) and ¹³C solid state NMR spectrum are not particularly restricted,but measurement is preferably carried out under the conditions hereindescribed.

A Crystalline Form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide anhydrate

The crystals (Form C) of the invention are anhydrate crystals consistingof a single crystal form of the compound (5b), and they are crystalscharacterized by having a diffraction peak at a diffraction angle(2θ±0.2°) of 11.4° or crystals characterized by having diffraction peaksat diffraction angles (2θ±0.2°) of 11.4° and 19.1°, in a powder X-raydiffraction. These characteristic peaks in a powder X-ray diffractionare not observed with the crystal obtained by the production processdisclosed in Patent document 1 (see Example 1B, Table 6 and FIG. 2below). The crystals (Form C) of the invention are also crystalscharacterized by having an absorption peak at a wavenumber of 1410±1cm⁻¹ or crystals having absorption peaks at a wavenumber of 1410±1 cm⁻¹and a wavenumber of 1443±1 cm⁻¹, in an infrared absorption spectrum(KBr). Furthermore, the crystals (Form C) of the invention are crystalscharacterized by having a peak at a chemical shift of approximately143.4 ppm or crystals characterized by having peaks at chemical shiftsof approximately 143.4 ppm and approximately 131.1 ppm, in a ¹³Csolid-state NMR spectrum.

Since the diffraction angle (2θ) in a powder X-ray diffraction generallyhas a diffraction angle error in the range of ±0.2°, the aforementionedvalues for the diffraction angle must be interpreted as including valueswithin a range of ±0.2°. Thus, the present invention encompasses notonly crystals whose peak diffraction angle in a powder X-ray diffractionmatches exactly, but also crystals whose peak diffraction angle matcheswith an error of ±0.2°.

Specifically, throughout the present specification, “having adiffraction peak at a diffraction angle (2θ±0.2°) of 11.4°” means“having a diffraction peak at a diffraction angle (2θ) in the range of11.2°-11.6°”, and “having a diffraction peak at a diffraction angle(2θ±0.2°) of 19.1°” means “having a diffraction peak at a diffractionangle (2θ) in the range of 18.9°-19.3°”.

Likewise, throughout the present specification, “having an absorptionpeak at a wavenumber of 1410±1 cm⁻¹” means “having an absorption peak ata wavenumber in the range of 1409-1411 cm⁻¹”, and “having an absorptionpeak at a wavenumber of 1443±1 cm⁻¹” means “having an absorption peak ata wavenumber in the range of 1442-1443 cm⁻¹”.

Throughout the present specification, “having a peak at a chemical shiftof approximately 143.4 ppm” means “having a peak substantiallyequivalent to a chemical shift of 143.4 ppm, when a ¹³C solid state NMRspectrum is measured under ordinary measuring conditions”. Also, “havinga peak at a chemical shift of approximately 131.1 ppm” as usedthroughout the present specification likewise means “having a peaksubstantially equivalent to a chemical shift of 131.1 ppm, when a ¹³Csolid state NMR spectrum is measured under ordinary measuringconditions”.

A Crystalline Form (Form A) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-Cyanobenzenesulfonamide Hydrate

The crystals (Form A) of the invention are hydrate crystals composed ofa single crystal form of the compound (5b), and they are crystalscharacterized by having a diffraction peak at a diffraction angle(2θ±0.2°) of 8.5° or crystals characterized by having diffraction peaksat diffraction angles (2θ±0.2°) of 8.5° and 25.8°, in a powder X-raydiffraction. The crystals (Form A) of the invention are also crystalscharacterized by having an absorption peak at a wavenumber of 616±1 cm⁻¹or crystals having absorption peaks at a wavenumber of 616±1 cm⁻¹ and awavenumber of 802±1 cm⁻¹, in an infrared absorption spectrum (KBr).Furthermore, the crystals (Form A) of the invention are crystalscharacterized by having a peak at a chemical shift of approximately134.7 ppm or crystals characterized by having peaks at chemical shiftsof approximately 134.7 ppm and approximately 126.3 ppm, in a ¹³C solidstate NMR spectrum.

Since the diffraction angle (2θ) in a powder X-ray diffraction generallyhas a diffraction angle error in the range of ±0.2°, the aforementionedvalues for the diffraction angle must be interpreted as including valueswithin a range of ±0.2°. Thus, the present invention encompasses notonly crystals whose peak diffraction angle in a powder X-ray diffractionmatches exactly, but also crystals whose peak diffraction angle matcheswith an error of ±0.2°.

Throughout the present specification, “having a diffraction peak at adiffraction angle (2θ±0.2°) of 8.5°” means “having a diffraction peak ata diffraction angle (2θ) in the range of 8.3°-8.7°”, and “having adiffraction peak at a diffraction angle (2θ±0.2°) of 25.8°” means“having a diffraction peak at a diffraction angle (2θ) in the range of25.6°-26.0°”.

Likewise, throughout the present specification, “having an absorptionpeak at a wavenumber of 616±1 cm⁻¹” means “having an absorption peak ata wavenumber in the range of 615-617 cm⁻¹”, and “having an absorptionpeak at a wavenumber of 802±1 cm⁻¹” means “having an absorption peak ata wavenumber in the range of 801-803 cm⁻¹”.

Throughout the present specification, “having a peak at a chemical shiftof approximately 134.7 ppm” means “having a peak substantiallyequivalent to a chemical shift of 134.7 ppm, when a ¹³C solid state NMRspectrum is measured under ordinary measuring conditions”. Also, “havinga peak at a chemical shift of approximately 126.3 ppm” as usedthroughout the present specification means “having a peak substantiallyequivalent to a chemical shift of 126.3 ppm, when a ¹³C solid state NMRspectrum is measured under ordinary measuring conditions”.

The crystals (Form A) of the invention may be obtained, for example, byrecrystallization of the crystals (Form C) of the invention from a mixedsolvent of ethanol and water.

Process for Preparing a Crystalline Form (Form C) (CrystallizationMethod)

The crystals (Form C) of the invention may be stably produced on anindustrial scale by producing the compound (5b) according to Example 1of Patent document 1 or Production Example 3A of the presentspecification, and then crystallizing the compound (5b) from a specificsolvent. The compound (5b) used for crystallization may be in any form.That is, it may be a hydrate or anhydrate, amorphous or crystalline(including combinations of multiple crystal forms) compound, or amixture thereof.

The solvent used for crystallization is a simple solvent selected fromthe group consisting of n-propyl alcohol, isopropyl alcohol, n-butylalcohol, s-butyl alcohol, t-butyl alcohol and water, or a mixed solventthereof. A mixed solvent is preferably a mixture of two differentsolvents selected from the group listed above. Preferred solvents are asimple solvent of isopropyl alcohol or s-butyl alcohol, a mixed solventof s-butyl alcohol and water or a mixed solvent of isopropyl alcohol andwater, more preferred solvents are a mixed solvent of s-butyl alcoholand water or a mixed solvent of isopropyl alcohol and water, and evenmore preferred solvent is a mixed solvent of s-butyl alcohol and water.

The mixing ratio (volume ratio) when using a mixed solvent of s-butylalcohol and water is preferably 3:1-5:1, more preferably 3.9:1-4.1:1 andeven more preferably 4:1.

The mixing ratio (volume ratio) when using a mixed solvent of isopropylalcohol and water is preferably 5:1-100:1, more preferably 9:1-100:1,even more preferably 9.9:1-10.1:1 and most preferably 10:1.

The amount of solvent used may be appropriately selected between theminimum amount in which the compound (5b) will dissolve by heating andthe maximum amount at which the yield of the crystals is notsignificantly reduced, and it is preferably a 3-40 fold amount (v/w),more preferably a 10-20 fold amount (v/w), even more preferably a 15-17fold amount (v/w) and most preferably a 15.7-16.3 fold amount (v/w), interms of the volume ratio with respect to the weight of the compound(5b).

The temperature for dissolution of the compound (5b) may beappropriately selected as the temperature at which the compound (5b)will dissolve in the solvent, but it is preferably from 75° C. toheating reflux temperature. The cooling during crystallization ispreferably carried out while suitably adjusting the cooling rate inconsideration of the effect on quality and grade of the crystals, andgradual cooling (cooling at a rate of 40° C./hr or slower) is preferred.More preferably, the cooling rate is 5-20° C./hr and even morepreferably it is about 10° C./hr. The final crystallization temperaturemay be appropriately selected in view of the yield and quality of thecrystals, but it is preferably from room temperature to 0° C., morepreferably 9-5° C. and even more preferably 6.5-7.5° C.

The precipitated crystals may be separated by an ordinary filtrationprocedure, washed with an appropriate solvent if necessary, and thendried to afford the desired crystals. The solvent used for washing ofthe crystals is the same as the crystallization solvent, and ispreferably s-butyl alcohol.

When the crystals separated by the filtration procedure consist (mainly)of anhydrate crystals (Form C), drying may be accomplished by merelystanding in air, but in the case of mass production this is notefficient, and therefore drying by heating is preferred. The dryingtemperature may be appropriately selected depending on the productionvolume, but it is preferably 40-130° C., more preferably 65-75° C. andeven more preferably 70° C. The drying time may be appropriatelyselected as a time up to which the residual solvent falls below aprescribed volume, depending on the production volume, drying apparatusand drying temperature. The drying may be carried out under an airflowor under reduced pressure, but it is preferably carried out underreduced pressure. The degree of pressure reduction may be appropriatelyselected depending on the production volume, drying apparatus and dryingtemperature.

Process for Preparing a Crystalline Form (Form C) (Thermal TransitionMethod)

The crystals (Form C) may also be produced by thermal transition of thecompound (5b). The compound (5b) used for thermal transition may be inany form. That is, it may be a hydrate or anhydrate, amorphous orcrystalline (including combinations of multiple crystal forms) compound,or a mixture thereof. A particularly preferred form is hydrate crystalsof the compound (5b), or a mixture of anhydrate crystals of the compound(5b) and hydrate crystals of the compound (5b). The mixture may be, forexample, a mixture obtained by rapid cooling during recrystallization ofthe compound (5b) (see Examples 2B and 1D of the present specification).

Heat drying of the compound (5b) with a heat drying apparatus can afforda crystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide anhydrate.

The heating temperature may be appropriately selected depending on theproduction volume, but is preferably 80-130° C., more preferably119-121° C. and even more preferably 120° C. The drying time may beappropriately selected as a time up to which the residual solvent fallsbelow a prescribed volume, depending on the production volume, dryingapparatus and drying temperature, but it is preferably between 10minutes and 12 hours and more preferably between 30 minutes and 3 hours.The drying may be carried out under an airflow or under reducedpressure, but it is preferably carried out under reduced pressure. Thedegree of pressure reduction may be appropriately selected depending onthe production volume, drying apparatus and drying temperature.

The compound (5b) may also be suspended in water, stirred while heatingand then filtered to afford the crystals (Form C). The amount of waterused is not particularly restricted, but is preferably a 5-30 foldamount (v/w), more preferably an 18-22 fold amount (v/w) and even morepreferably a 20-fold amount (v/w) with respect to the hydrate-containingcrystals to be suspended. The temperature for heated stirring may be60-90° C., preferably 75-85° C. and more preferably 80° C. The time forheated stirring may be 1-24 hours, preferably 3-18 hours and morepreferably 16-18 hours.

The obtained anhydrate crystals may be subjected to additional dryingwith the same method and conditions as the drying method and conditionsdescribed for the crystallization method.

The crystals (Form C) obtained by the process described above consist ofa single crystal form which is stable, does not readily convert to othercrystal forms or an amorphous form and has satisfactory physicalproperties such as lack of hygroscopicity, and they are thereforesuitable for formulation.

Pharmaceutical Composition Comprising Crystals of the Invention

The use of the compound (5b) as an antitumor agent is disclosed indetail in Patent document 1, and the crystals of the invention may beused in a similar fashion as the active ingredient of an antitumoragent. The entirety of the disclosure of Patent document 1 isincorporated by reference into the disclosure of the presentspecification. Moreover, the crystals (Form C) of the invention havesatisfactory stability and physical properties and are hence the mostsuitable form for use of the compound (5b) as the active ingredient ofan antitumor agent.

The crystals of the invention may be formulated by an ordinary methodinto tablets, powder, fine powder, granules, coated tablets, capsules,syrup, lozenges, an inhalant, suppository, injection, ointment, eyeointment, eye drop, nose drop, ear drop, pap, lotion or the like. Forformulation there may be employed commonly used excipients, binders,lubricants, coloring agents, taste correctives and, if necessary,stabilizers, emulsifiers, absorption accelerators, surfactants, pHadjustors, antiseptics, antioxidants and the like, while othercomponents ordinarily used as starting materials for drug formulationmay also be added according to common procedures.

As examples of such components there may be mentioned animal orvegetable oils such as soybean oil, beef tallow and syntheticglycerides; hydrocarbons such as liquid paraffin, squalene and solidparaffin; ester oils such as octyldodecyl myristate and isopropylmyristate; higher alcohols such as cetostearyl alcohol and behenylalcohol; silicone resins; silicone oils; surfactants such aspolyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerinfatty acid ester, polyoxyethylenesorbitan fatty acid ester,polyoxyethylene hydrogenated castor oil andpolyoxyethylene-polyoxypropylene block copolymer; water-soluble polymerssuch as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer,polyethylene glycol, polyvinylpyrrolidone and methylcellulose; loweralcohols such as ethanol and isopropyl alcohol; polyhydric alcohols suchas glycerin, propylene glycol, dipropylene glycol and sorbitol; sugarssuch as glucose and sucrose; inorganic powders such as silicicanhydride, magnesium aluminum silicate and aluminum silicate, purifiedwater, and the like.

As examples of excipients there may be mentioned lactose, corn starch,white soft sugar, glucose, mannitol, sorbit, crystalline cellulose,silicon dioxide and the like, as examples of binders there may bementioned polyvinyl alcohol, polyvinyl ether, methylcellulose,ethylcellulose, gum Arabic, tragacanth gum, gelatin, shellac,hydroxypropylmethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene blockpolymer, meglumine and the like, as examples of disintegrators there maybe mentioned starch, agar, gelatin powder, crystalline cellulose,calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin,pectin, carboxymethylcellulose calcium and the like, as examples oflubricants there may be mentioned magnesium stearate, talc, polyethyleneglycol, silica, hydrogenated vegetable oils and the like, as examples ofcoloring agents there may be mentioned those approved for addition topharmaceuticals, and as examples of taste correctives there may bementioned cocoa powder, menthol, aromatic powder, peppermint oil,camphor, cinnamon powder and the like.

For production of an oral preparation, the compound of the invention orits pharmacologically acceptable salt may be combined with an excipientand, if necessary, a binder, disintegrator, lubricant, coloring agent,taste corrective or the like and then made into a powder, fine powder,granules, tablets, coated tablets or capsules.

Also, there is no restriction against sugar-coating and, if necessary,other appropriate coating of the tablets or granules.

For production of a liquid preparation such as a syrup or pharmaceuticalpreparation for injection, the compound of the invention or itspharmacologically acceptable salt may be combined with a pH adjustor,solubilizer, isotonizing agent or the like, and if necessary, with adissolving aid, stabilizers or the like, and formulated by an ordinarymethod.

The method of producing an external preparation is not particularlyrestricted, and may be according to an ordinary method. Specifically, asbase materials for pharmaceutical preparation there may be used variousmaterials ordinarily employed for pharmaceuticals, quasi drugs,cosmetics and the like. As examples of specific base materials to beused there may be mentioned materials such as animal and vegetable oils,mineral oils, ester oils, waxes, higher alcohols, fatty acids, siliconeoils, surfactants, phospholipids, alcohols, polyhydric alcohols,water-soluble polymers, clay minerals, purified water and the like, andif necessary there may also be added pH adjustors, antioxidants,chelating agents, antiseptic/mildew resistant agents, coloring agents,aromatics and the like, although base materials for an externalpreparation of the invention are not limited to these. If necessarythere may also be included components such as circulation promoters,bactericidal agents, antiflash agents, cell activators, vitamins, aminoacids, humectants, keratolytic agents and the like. The amounts of suchbase materials are the amounts which give concentrations indicated forproduction of ordinary external preparations.

The form of administration of the crystals of the invention is notparticularly restricted, and may be oral administration or parenteraladministration by an ordinarily employed method. For example, thecrystals may be administered after formulation into tablets, powder,granules, capsules, syrup, lozenges, an inhalant, suppository,injection, ointment, eye ointment, eye drop, nose drop, ear drop, pap,lotion or the like. The dosage of a pharmaceutical according to theinvention may be appropriately selected depending on patient age,gender, body weight, severity of symptoms, particular type of condition,and on the type of dosage form or salt.

The following are examples of pharmaceutical formulations comprising acrystalline form (Form C) ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide anhydrate(compound (5b), crystals Form C), to be used for treatment or preventionin humans.

Whole formulation for 100 mg preparation (content per tablet)

TABLE 1 Content Ingredient Purpose of use (mg) Compound (5b), crystalsForm C principal agent 100.0 Mannitol excipient 123.8 Corn starchexcipient 36.0 Low substituted disintegrator 48.0 hydroxypropylcelluloseHydroxypropylcellulose binder 9.6 Magnesium stearate lubricant 2.6Hydroxypropylmethylcellulose coating agent 5.7 Macrogol coating agent1.2 Talc coating agent 2.6 Titanium oxide coating agent 0.45 Yellow ironoxide coloring agent 0.05 Total 330 mgWhole formulation for 50 mg preparation (content per tablet)

TABLE 2 Content Ingredient Purpose of use (mg) Compound (5b), crystalsForm C principal agent 50.0 Mannitol excipient 61.9 Corn starchexcipient 18.0 Low substituted disintegrator 24.0 hydroxypropylcelluloseHydroxypropylcellulose binder 4.8 Magnesium stearate lubricant 1.3Hydroxypropylmethylcellulose coating agent 3.4 Macrogol coating agent0.7 Talc coating agent 1.6 Titanium oxide coating agent 0.27 Yellow ironoxide coloring agent 0.03 Total 166 mgWhole formulation for 10 mg preparation (content per tablet)

TABLE 3 Content Ingredient Purpose of use (mg) Compound (5b), crystalsForm C principal agent 10.0 Mannitol excipient 89.9 Corn starchexcipient 38.0 Low substituted disintegrator 16.0 hydroxypropylcelluloseHydroxypropylcellulose binder 4.8 Magnesium stearate lubricant 1.3Hydroxypropylmethylcellulose coating agent 3.4 Macrogol coating agent0.7 Talc coating agent 1.6 Titanium oxide coating agent 0.27 Yellow ironoxide coloring agent 0.03 Total 166 mgWhole formulation for 2 mg preparation (content per tablet)

TABLE 4 Content Ingredient Purpose of use (mg) Compound (5b), crystalsForm C principal agent 2.0 Mannitol excipient 95.9 Corn starch excipient40.0 Low substituted disintegrator 16.0 hydroxypropylcelluloseHydroxypropylcellulose binder 4.8 Magnesium stearate lubricant 1.3Hydroxypropylmethylcellulose coating agent 3.4 Macrogol coating agent0.7 Talc coating agent 1.6 Titanium oxide coating agent 0.27 Yellow ironoxide coloring agent 0.03 Total 166 mg

The pharmaceutical preparations having the formulations listed above maybe obtained by ordinary pharmaceutical protocols.

EXAMPLES

The present invention will now be explained in greater detail andspecifically by the following examples, with the understanding that theinvention is in no way limited to the examples.

Example 1A Production of 3-cyano-4-methyl-7-nitro-1H-indole

To 740 mL of dimethylformamide was added 235 mL (2.52 mol) ofphosphorous oxychloride at 0° C., followed by stirring at 0° C. for 0.5hour. To the reaction mixture was then added a solution of 370 g (2.10mol) of 4-methyl-7-nitro-1H-indole (WO00/50395) in dimethylformamide(1110 mL) at 0° C., followed by heating and stirring at 60° C. for 2hours.

To the reaction mixture was then added dropwise a solution of 292 g(4.20 mol) of hydroxylamine hydrochloride in dimethylformamide (1850 mL)with keeping the internal temperature below 80° C., followed by heatingand stirring at 60° C. for 40 minutes. After adding 11.1 L of ice waterto the reaction mixture while cooling in an ice bath, the mixture wasfurther stirred overnight. The precipitated crystals were collected byfiltration and washed with water. The crystals were suspended in 11.1 Lof water, 1N solution of sodium hydroxide was added to the suspensionfor adjustment to pH 7, and then the crystals were collected byfiltration and washed with water to give 412 g of the title compound(yield: 97.6%).

HPLC analysis confirmed that the obtained compound was identical to the3-cyano-4-methyl-7-nitro-1H-indole described in WO00/50395.

(HPLC Conditions)

Mobile phase: CH₃CN/H₂O/70% HClO₄=500/500/1 (v/v/v)Flow rate: 1.0 mL/min

Detection: UV (254 nm) Column: YMC-Pack Pro C18 250×4.6 mm Example 2AProduction of 7-amino-3-cyano-4-methyl-1H-indole

After suspending 400 g (1.99 mol) of the3-cyano-4-methyl-7-nitro-1H-indole obtained in Example 1A in a mixtureof 6 L of ethyl acetate and 6 L of methanol, the suspension wassubjected to hydrogenation in the presence of 40 g of 10%palladium-carbon at ordinary temperature, 4 atmospheres. After removingthe catalyst by filtration, the filtrate was treated with activatedcarbon and concentrated to give crude crystals. The crude crystals weredissolved in 6 L of 1,2-dimethoxyethane at an external temperature of60° C., and then 12 L of water was added dropwise. Upon confirmingprecipitation of crystals, the mixture was stirred for 1.5 hours whilecooling in an ice bath and filtered, and the crystals were washed twicewith water (1 L). The crystals were air-dried at 50° C. for 16 hours togive 289 g of the title compound (yield: 84.8%).

HPLC analysis confirmed that the obtained compound was identical to the7-amino-3-cyano-4-methyl-1H-indole described in WO00/50395.

(HPLC Conditions)

Mobile phase: CH₃CN/H₂O/70% HClO₄=400/600/1 (v/v/v)Flow rate: 1.0 mL/min

Detection: UV (282 nm) Column: YMC-Pack Pro C18 250×4.6 mm Example 3AProduction ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form C))

To a suspension of 5.0 g (29 mmol) of the7-amino-3-cyano-4-methyl-1H-indole obtained in Example 2A and 6.48 g (32mmol) of 3-cyanobenzenesulfonyl chloride [CAS No. 56542-67-7] in 150 mLof methyl acetate, were added 75 mL of water and 2.83 mL (35 mmol) ofpyridine, followed by stirring for 2 hours and 40 minutes. After adding0.73 mL (9 mmol) of concentrated hydrochloric acid to the reactionmixture, liquid-liquid separation was performed and the organic layerwas washed with a mixture of 75 mL of water and 17.5 mL of ethanol.Activated carbon was added to the organic layer and the mixture wasstirred at 45-50° C. for 30 minutes, and then filtered and concentrated.To thus obtained crude crystals were added 96 mL of 2-butanol and 24 mLof water for dissolution at 75° C., and the solution was cooled to 7° C.at approximately 10° C./hr and stirred overnight. The precipitatedcrystals were collected by filtration and washed twice with 10 mL of2-butanol to give 8.17 g (wet weight) of crystals of the title compound.The crystals were dried under reduced pressure at 70° C. for 2 hours togive 7.54 g of crystals of the title compound.

HPLC analysis confirmed that the obtained compound was identical to theN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide describedin WO00/50395.

(HPLC Conditions)

Mobile phase: CH₃CN/H₂O/70% HClO₄=500/500/1 (v/v/v)Flow rate: 1.0 mL/min

Detection: UV (282 nm) Column: YMC-Pack Pro C18 250×4.6 mm

A powder X-ray diffraction pattern for the obtained crystals is shown inFIG. 1, and the diffraction angle (2θ) peak and peak intensity are shownin Table 5.

TABLE 5 INTERPLANAR HALF PEAK No. 2 θ SPACING INTENSITY WIDTH I/Io 111.420 7.74203 2122 0.210 55 2 13.040 6.78353 913 0.210 24 3 14.3806.15437 778 0.300 20 4 15.200 5.82415 717 0.210 19 5 15.540 5.69748 2200.210 6 6 16.380 5.40714 1013 0.210 26 7 17.000 5.21131 960 0.210 25 819.080 4.64763 3925 0.240 100 9 19.440 4.56237 505 0.150 13 10 19.7804.48471 1512 0.240 39 11 20.360 4.35824 470 0.210 12 12 20.900 4.24684543 0.210 14 13 22.500 3.94833 1295 0.150 33 14 22.620 3.92765 14370.270 37 15 23.160 3.83728 295 0.120 8 16 23.950 3.71094 920 0.330 24 1724.400 3.64501 890 0.180 23 18 24.520 3.62744 952 0.150 25 19 24.9803.56168 917 0.240 24 20 25.560 3.48216 693 0.210 18 21 26.260 3.390901230 0.270 32 22 26.760 3.32867 823 0.240 21 23 28.840 3.09315 12770.210 33 24 29.620 3.01345 270 0.180 7

Example 1B Production ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (mixtureconsisting mainly of anhydrate crystals (Form B))

Crystals of the title compound were synthesized using the same reactionconditions and recrystallization conditions as for theN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide describedin WO00/50359.

To a solution of 7-amino-3-cyano-4-methyl-1H-indole (10 g, 58.4 mmol) intetrahydrofuran (200 ml) were added pyridine (20 ml) and3-cyanobenzenesulfonyl chloride (12.5 g), followed by stirring at roomtemperature for 3.5 hours. After further adding 2N hydrochloric acid(100 ml), extraction was performed with ethyl acetate. The organic layerwas washed with water (twice) and brine in that order, dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1-3:2). A mixed solvent of ethanol-hexane (1:2)was added thereto, and after sonication, the precipitate was collectedby filtration and washed with a mixed solvent of ethanol-hexane (1:3).The mixture was dried overnight under reduced pressure to give the titlecompound (9.33 g, 27.7 mmol, 47% yield).

¹H-NMR spectrum (DMSO-d₆) δ (ppm): 2.58 (3H, s), 6.52 (1H, d, J=7.6 Hz),6.80 (TH, d, J=7.6 Hz), 7.74 (1H, m), 7.92 (1H, d, J=8.0 Hz), 8.12 (2H,m), 8.19 (11H, d, J=3.2 Hz), 10.13 (1H, s), 12.03 (1H, s).

A powder X-ray diffraction pattern for the obtained crystals is shown inFIG. 2, and the diffraction angle (2θ) peak and peak intensity are shownin Table 6.

TABLE 6 HALF RELATIVE PEAK No. 2 θ WIDTH d-VALUE INTENSITY INTENSITY 15.960 0.235 14.8167 3492 49 2 8.100 0.212 10.9063 2820 40 3 8.440 0.18810.4677 1968 28 4 11.920 0.259 7.4184 4067 57 5 14.120 0.282 6.2671 7103100 6 15.120 0.259 5.8548 2142 30 7 16.400 0.165 5.4006 2330 33 8 17.6600.141 5.0180 1905 27 9 17.960 0.212 4.9349 1998 28 10 19.240 0.3064.6093 5707 80 11 21.380 0.235 4.1526 2443 34 12 21.940 0.282 4.04785502 77 13 23.020 0.212 3.8603 2602 37 14 23.580 0.165 3.7699 3172 45 1523.900 0.400 3.7201 3958 56 16 24.540 0.282 3.6245 2812 40 17 25.8400.165 3.4451 4302 61 18 26.520 0.212 3.3582 3045 43 19 27.540 0.3763.2361 3265 46 20 28.380 0.118 3.1422 2655 37 21 28.520 0.188 3.12712435 34

It was attempted to produce identical crystals by the same process asExample 1B, but the powder X-ray diffraction pattern did not match. Inother words, the crystals obtained in Example 1B were presumably not ofa single crystal form but were a mixture of multiple crystal forms.Moreover, it is believed that a single crystal form cannot be producedby the process of Example 1B.

Example 2B Production ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form C)) (Alternative method 1)

After suspendingN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (mixtureconsisting mainly of hydrate crystals) (1.00 g) obtained by the sameprocess as Example 1B in isopropyl alcohol (5.0 ml), the mixture washeated to reflux. Isopropyl alcohol (16.0 ml) was gradually addedthereto, for complete dissolution of the crystals. The solution washeated to reflux for 30 minutes, and then heating of the oil bath wasstopped and stirring was performed for 12 hours. The precipitatedcrystals were collected by filtration, and the crystals were washed withisopropyl alcohol (2 ml×3) and suction-dried at room temperature for 10minutes. Thus obtained crystals were dried at 50° C. for 13.5 hours, andthen pounded in a mortar. This was dried at 50° C. for 13 hours to givea mixture (744 mg) of hydrate crystals and anhydrate crystals (Form C)of N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide, aslight yellow to light brown crystals.

A 200 mg portion thereof was dried at 120° C. for 30 minutes to givecrystals of N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide(194 mg).

When a powder X-ray diffraction pattern of the obtained crystals wasmeasured, it matched the diffraction pattern of the crystals obtained inExample 1C, confirming that the obtained crystals were identicalcrystals to the crystals obtained in Example 1C (anhydrate crystals(Form C)).

Example 1C Production ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form C)) (Alternative method 2)

After suspending 2.50 kg (14.6 mol) of7-amino-3-cyano-4-methyl-1H-indole and 3.24 kg (16.06 mol) of3-cyanobenzenesulfonyl chloride [CAS No. 56542-67-7] in 25 L of methylacetate, 87.5 L of methyl acetate and 37.5 L of water were addedthereto. Next, 1.39 kg (17.52 mol) of pyridine was added dropwise andthe mixture was stirred for 2 hours.

After adding 0.36 L (4.38 mol) of concentrated hydrochloric acid to thereaction mixture, it was subjected to liquid-liquid separation and theorganic layer was washed with a mixture of 37.5 L of water and 8.8 L ofethanol. After adding activated carbon to the organic layer and stirringat 50° C. for 30 minutes, the mixture was filtered and concentrated. Tothis was added 30 L of isopropyl alcohol, and after re-concentration, 91L of isopropyl alcohol and 9.1 L of water were added and the mixture washeated to 70° C. Dissolution was confirmed after 2 hours, and thenclarifying filtration was performed and 11.4 L of isopropyl alcohol and1.1 L of water were added. The solution was slowly cooled to 7° C. at10° C./hr (with introduction of seed crystals at 64° C.), and afterstirring overnight at 7° C., the crystals were collected by filtration.The crystals were dried at 70° C. under reduced pressure to give 3.6 kgof the title compound as a white crystalline powder (yield: 73%).

The moisture content of the obtained white crystalline powder wasmeasured by the Karl Fischer method to be 0.1%, confirming that theobtained crystals were anhydrate crystals. HPLC analysis also confirmedthat the obtained crystals wereN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide.

(HPLC Conditions)

Mobile phase: CH₃CN/H₂O/70% HClO₄=500/500/1 (v/v/v)Flow rate: 1.0 ml/min

Detection: UV (282 nm) Column: YMC-Pack Pro C18 250×4.6 mm

Column temperature: 25° C.Retention time: 8.3 min

A powder X-ray diffraction pattern for the obtained crystals is shown inFIG. 3, and the diffraction angle (2θ) peak and peak intensity are shownin Table 7.

TABLE 7 2 theta (degree) Relative Intensity 11.4 47 13.0 24 14.4 20 15.221 16.4 30 17.0 16 19.1 100 19.8 36 20.4 12 20.9 15 22.6 37 24.0 25 24.528 25.0 27 25.6 10 26.3 35 26.8 23 28.8 35 31.6 24 32.7 10

A ¹³C solid-state NMR spectrum for the obtained crystals is shown inFIG. 5, and the chemical shifts are listed in Table 8.

TABLE 8 Chemical Shift (ppm) 143.4 137.7 136.9 134.2 131.1 128.5 126.4125.8 124.3 120.0 118.8 115.8 111.0 84.5 19.4

An infrared spectrum (KBr) for the obtained crystals is shown in FIG. 7,and the wavenumbers (cm⁻¹) and transmittances (% T) of the absorptionpeak are shown in Table 9.

TABLE 9 Wavenumber (cm−1) % T Wavenumber (cm−1) % T 32′2 5 1087 23 295426 1060 38 2872 26 984 25 2242 22 939 41 2223 7 905 25 17′5 47 839 4516′7 49 819 38 15′9 29 795 32 1472 42 754 33 1443 12 690 19 14′0 20 67616 1337 12 652 26 13′6 17 625 24 1260 32 607 28 1207 33 588 20 1178 32559 17 1158 6 518 14 1102 32 420 45

Example 1D Production ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (hydratecrystals (Form A))

N-(3-Cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (31.8 g)was dissolved in isopropyl alcohol (954 ml) and water (9.5 ml) at anexternal temperature of 80° C. Anhydrate seed crystals (95.4 mg) wereadded, and rapid ice-cooling was carried out. After stirring for 30minutes, the crystals were collected by filtration, washed twice withisopropyl alcohol (60 ml), and dried at 19° C. for 3.5 hours underreduced pressure to give white crystals of the title compound (28.1 g).A powder X-ray diffraction pattern of the obtained crystals wasmeasured, and it matched the diffraction pattern of the crystalsobtained in Example 1F, confirming that the crystals obtained in thisexample were of the same type as the crystals obtained in Example 1F.

Example 2D Production ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form C)) (Alternative method 3)

After suspending theN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (5 g)obtained in Example 1D in water (100 ml), the mixture was heated andstirred at 80° C. for 17 hours It was then allowed to cool down to roomtemperature, and then the crystals were collected by filtration, washedwith water (20 ml) and dried under reduced pressure at 70° C. for 22hours to give crystals of the title compound (4.20 g) (yield: 97.7%).

A powder X-ray diffraction pattern of the obtained crystals wasmeasured, and it matched the diffraction pattern of the crystalsobtained in Example 1C, confirming that the obtained crystals wereidentical crystals to the crystals obtained in Example 1C (anhydratecrystals (Form C)).

Example 1E Production ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form B))

After dissolvingN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form C), 1.0 g) in a mixed solution of dehydrated ethanol (36mL) and water (6 mL) in a water bath at 70° C., the solution was allowedto stand in ice water. The precipitated crystals were filtered, and theobtained crystals were dried at 200° C. to giveN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form B)).

A powder X-ray diffraction pattern for the obtained crystals is shown inFIG. 9.

Example 1F Production ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (hydratecrystals (Form A))

After dissolvingN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (anhydratecrystals (Form C), 1.0 g) in a mixed solution of dehydrated ethanol (36mL) and water (6 mL) in a water bath at 70° C., the solution was allowedto stand in an ice water bath. The precipitated crystals were filteredto give N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide(hydrate crystals (Form A)).

A powder X-ray diffraction pattern for the obtained crystals is shown inFIG. 4, and the diffraction angle (2θ) peak and peak intensity are shownin Table 10.

TABLE 10 2 theta (degree) Relative Intensity 8.5 100 11.8 8 13.9 14 15.120 16.5 61 17.0 17 17.7 11 19.9 16 20.3 16 21.8 8 22.2 8 23.9 23 24.5 1325.8 41 26.3 39 28.6 13 30.2 9 34.4 7

A ¹³C solid-state NMR spectrum for the obtained crystals is shown inFIG. 6, and the chemical shifts are listed in Table 11.

TABLE 11 Chemical Shift (ppm) 139.9 136.5 134.7 131.7 130.5 129.9 128.2126.3 122.4 119.9 118.4 116.9 114.1 111.7 82.′ 16.′

An infrared spectrum (KBr) for the obtained crystals is shown in FIG. 8,and the wavenumbers (cm⁻¹) and transmittances (% T) of the absorptionpeak are shown in Table 12.

TABLE 12 Wavenumber (cm−1) % T 3749 48 3650 35 3400 12 3131 23 3071 282916 42 2233 32 2217 17 1846 60 1734 58 1621 47 1517 25 1472 37 1422 131389 40 1347 13 1320 23 1244 46 1206 34 1179 38 1160 11 1139 17 1108 291091 32 1060 50 982 47 964 54 928 51 907 47 850 52 813 42 802 36 702 26682 22 635 28 616 24 597 32 572 26 556 29 526 42 508 28 420 51

(Powder X-Ray Diffraction Measurement)

Powder X-ray diffraction measurements for the crystals obtained in eachof the examples was carried out under the following measuringconditions.

[Measuring Conditions A]

X-rays: CuKα raysTube voltage: 40 kVTube current: 20 mADivergence slit: 1°Receiving slit: 0.15 mmScattering slit: 1°Scan speed: 2°/min

[Measuring Conditions B]

X-rays: CuKα raysTube voltage: 40 kVTube current: 200 mADivergence slit: ½°Receiving slit: 0.3 mmScattering slit: ½°Scan speed: 2°/min

The crystals obtained in Example 3A were measured under measuringconditions A above, and the crystals obtained in Examples 1B, 1C, 1E and1F were measured under measuring conditions B above.

(¹³C solid state NMR spectroscopy)

¹³C solid state NMR spectrum measurements of the crystals obtained inExamples 1C and 1F were conducted under the following conditions.

Measuring temperature: Room temperature (˜22° C.)Standard substance: Silicone rubber (internal standard: 1.56 ppm)Measuring nucleus: ¹³C (75.188829 MHz)Pulse repeat time: 70 sec (Form A: Example 1F), 150 sec (Form C: Example1C)Pulse mode: CP/MAS measurement (VACPX-pm)

(Infrared Absorption Spectroscopy (Kbr))

Infrared spectrum measurements of the crystals obtained in Examples 1Cand 1F were conducted by the potassium bromide disk method.

Test Example 1 Purity of crystals obtained in Example 1B

The impurity content in the crystals obtained in Example 1B was measuredby HPLC.

(HPLC Conditions)

Column: ODS column (inner diameter=4.6 mm, column length=250 mm,particle size=5 μm)Column temperature: 30° C.Detection wavenumber: 282 nmFlow rate: 1.0 mL/minMobile phase:Solution A: CH₃CN/H₂O/70% HClO₄=100/900/1 (v/v/v)Solution B: CH₃CN/H₂O/70% HClO₄=900/100/1 (v/v/v)

The gradient program is shown in Table 13.

TABLE 13 Time (min) Solution B (%) Initial 35 40 100 50 100

(Impurity Content Calculation Method)

All of the peaks and peak areas were calculated from the chromatogram,and the impurity amount for each peak (except for the peak ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide) wascalculated according to the following formula.

Individual impurity content (%)=(individual impurity peak area)/(totalof all peak areas)×100

Peaks with impurity contents of 0.05% or greater were recorded asimpurity peaks, and their total was recorded as the impurity content ofthe crystals.

Impurity content (%)=Total of individual impurity contents (%)

The results of HPLC analysis demonstrated that the crystals obtained inExample 1B contained 2.17% impurities.

Test Example 2 Solid Stability Against Light

The crystals obtained in Example 1C, Example 1E and Example 1F werestored for 1 month and 3 months at 25° C./1000 Lx (LT-120D3J LightStability Tester by Nagano Science, Japan), and then the impuritycontents were measured by HPLC.

(HPLC Conditions)

HPLC was conducted under the same conditions as in Test Example 1,except that elution was performed with the gradient program shown inTable 14.

TABLE 14 Time (min) Solution B (%) Initial 35 25 35 40 100 50 100

The impurity content of the crystals was determined by the same methodas described for Test Example 1. The impurity contents of the crystalsobtained in different examples before and after storage are listed inTable 15. As shown in Table 15, no change in impurity content before andafter storage was seen for Example 1F and Example 1C, but the impuritycontent increased before and after storage for Example 1E. That is, thecrystals obtained in Examples 1F and 1C (Form A and Form C) clearly hadhigher stability against light.

TABLE 15 Impurity content (%) Storage conditions Example 1F Example 1EExample 1C Before storage 0.42 0.50 0.51 25° C./1000 Lx/1 month 0.410.83 0.51 25° C./1000 Lx/3 months 0.51 4.44 0.51

These results demonstrated that highly pure crystals can be obtained bythe process for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide (Form C)according to the invention, and that the obtained crystals (Form C) havehigh stability against light and properties suitable for pharmaceuticalformulation.

INDUSTRIAL APPLICABILITY

The present invention provides crystallineN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having asingle crystal form and excellent stability against light, as well as aprocess for preparing the same. The crystals may be used as the activeingredient of a pharmaceutical composition, and especially are suitablefor use as the active ingredient of an angiogenesis inhibitor, antitumoragent, pancreatic cancer therapeutic agent, colorectal cancertherapeutic agent, gastric cancer therapeutic agent, breast cancertherapeutic agent, prostate cancer therapeutic agent, lung cancertherapeutic agent, ovarian cancer therapeutic agent, cancer metastasisinhibitor, diabetic retinopathy therapeutic agent, rheumatoid arthritistherapeutic agent or angioma therapeutic agent.

1. A crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide havingpeaks at chemical shifts of approximately 143.4 ppm, 137.7 ppm, 136.9ppm, 134.2 ppm, 131.1 ppm, 128.5 ppm, 126.4 ppm, 125.8 ppm, 124.3 ppm,120.0 ppm, 118.8 ppm, 115.8 ppm, 111.0 ppm, 84.5 ppm and 19.4 ppm in a¹³C solid state NMR spectrum.
 2. A process for preparing a crystallineform of N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamideaccording to claim 1, comprising crystallizingN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide using asimple solvent selected from the group consisting of n-propyl alcohol,isopropyl alcohol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol andwater, or a mixed solvent thereof as a crystallization solvent.
 3. Theprocess according to claim 2, wherein the crystallization solvent is asimple solvent of isopropyl alcohol or s-butyl alcohol, or a mixedsolvent of s-butyl alcohol and water or a mixed solvent of isopropylalcohol and water.
 4. The process according to claim 2, wherein thecrystallization solvent is a mixed solvent of s-butyl alcohol and water(volume ratio=3:1-5:1) or a mixed solvent of isopropyl alcohol and water(volume ratio=9:1-10:1).
 5. The process according to claim 2, whereinthe crystallization solvent is a mixed solvent of s-butyl alcohol andwater (volume ratio=3.9:1-4.1:1).
 6. The process according to claim 2,wherein N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide isheated and dissolved in a solvent and then crystallized.
 7. The processaccording to claim 2, whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedand dissolved in a solvent and then crystallized by gradual cooling. 8.A process for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto claim 1, whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedat 80-130° C.
 9. A process for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto claim 1, whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedand stirred in water at 60-90° C.
 10. A process for preparing acrystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto claim 1, wherein a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate isheated at 80-130° C.
 11. A process for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide accordingto claim 1, wherein a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate isheated and stirred in water at 60-90° C.
 12. A crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having the¹³C solid state NMR spectrum substantially as depicted in FIG.
 5. 13. Aprocess for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having theX-ray diffraction pattern substantially as depicted in FIG. 3,comprising: crystallizingN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide using asimple solvent selected from the group consisting of n-propyl alcohol,isopropyl alcohol, n-butyl alcohol, s-butyl alcohol, t-butyl alcohol andwater, or a mixed solvent thereof as a crystallization solvent.
 14. Theprocess according to claim 13, wherein the crystallization solvent is asimple solvent of isopropyl alcohol or s-butyl alcohol, or a mixedsolvent of s-butyl alcohol and water or a mixed solvent of isopropylalcohol and water.
 15. The process according to claim 13, wherein thecrystallization solvent is a mixed solvent of s-butyl alcohol and water(volume ratio=3:1-5:1) or a mixed solvent of isopropyl alcohol and water(volume ratio=9: 1-10:1).
 16. The process according to claim 13, whereinthe crystallization solvent is a mixed solvent of s-butyl alcohol andwater (volume ratio=3.9:1-4.1:1).
 17. The process according to claim 13,wherein N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide isheated and dissolved in a solvent and then crystallized.
 18. The processaccording to claim 13, whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedand dissolved in a solvent and then crystallized by gradual cooling. 19.A process for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having theX-ray diffraction pattern substantially as depicted in FIG. 3, whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedat 80-130° C.
 20. A process for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having theX-ray diffraction pattern substantially as depicted in FIG. 3, whereinN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide is heatedand stirred in water at 60-90° C.
 21. A process for preparing acrystalline N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamidehaving the X-ray diffraction pattern substantially as depicted in FIG.3, wherein a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate isheated at 80-130° C.
 22. A process for preparing a crystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide having theX-ray diffraction pattern substantially as depicted in FIG. 3, wherein acrystalline form ofN-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonamide hydrate isheated and stirred in water at 60-90° C.